basic antimicrobial pharmacology
TRANSCRIPT
Basic Antimicrobial Pharmacology
Dr. Matthias Götte
Department of Medical Microbiology & Immunology
Faculty of Medicine & Dentistry
University of Alberta
Email: [email protected]
Date: September 15, 2020
Presenter Disclosure
MG received funding from Gilead Sciences Inc.
for mechanistic studies on Remdesivir.
Lecture Title: Date:
Learning Objectives
Provide a basic understanding of structure and
mechanisms of antivirals and antibiotics
Provide a basic understanding of mechanisms
associated with antimicrobial resistance (AMR)
Discuss therapeutic approaches designed to
overcome AMR
Lecture Title: Date:
Alignment with Learning Outcomes
Complex contributing factors to antimicrobial use
and the emergence and spread of AMR: a
biochemical perspective
Lecture Title: Date:
MSc Chemistry
PhD Biochemistry
HIV/HCV Lab
2000-2014 Emerging Pathogens
2014 - present
Matthias Götte, PhD
Professor and Chair
Department of Medical
Microbiology & Immunology
University of Alberta
SOURCE: Bean et al., 2013.
Emerging Viruses
Ebola Outbreaks 2014 and 2018
The novel coronavirus SARS-CoV-2 (Severe Acute
Respiratory Syndrome Coronavirus 2) is the causative
agent of COVID-19, first reported in December 2019.
WHO declares in March 2020 a pandemic.
Emerging Bacteria
Human Immunodeficiency Virus (HIV)
The 10 Leading Causes of Death in the US (1950 – 2000)
Strauss & Strauss 2008
”Triple Therapy”
Strauss & Strauss 2008
Fingers
Palm
Thumb
Viral Polymerases are Good Targets for Antiviral Drugs
HIV-1 Reverse Transcriptase
Castro et al., 2009; Nature Structural Biology
How do they function?
https://www.researchgate.net/figure/Mechani
sm-of-antiviral-action-of-AZT
AZT: the 1st HIV drug
N
H
O
C
H
3
O
N
O
Ho
O
H
Thymidine
N
H
O
C
H
3
O
N
O
Ho
N
3
N
H
O
C
H
3
O
N
O
Ho
O
N
N
H
2
N
O
Ho
O
H
Cytidine
O
N
N
H
2
N
O
S
Ho
AZT d4T
3TC
Different Nucleoside Analogue RT Inhibitors (NRTIs)
PP PP
P P
P
H
A
B
P
P
P
OHP
Chain-termination
Resistance To Antiviral Drugs
HIV exists as a mixture of
billions of different particles in
infected patients.
Why?
HIV and other viruses are
sloppy and make mistakes
during replication.
Why is this important?
Some of these viruses are
resistant to antiviral drugs.
HIV Levels Before Treatment HIV Levels on Treatment
Selection of Resistant Viruses on
Treatment
Take Your Medication to Keep Drug Levels
Sufficiently High
Monotherapy Fails
Triple Therapy Works
“Orange drugs” don’t work against resistant variants.
All three drugs are more effective and suppress the
emergence of resistant variants. AND “white and yellow
drugs” still work against resistant variants.
Why is the drug not working anymore?
Resistant variants contain mutations
that change the interaction with the
drug.
Drug Binding
Site
Altered Pocket
Reduces Binding
Drug Drug
Approved Anti-HIV Drugs
Initiation of
Triple Therapy
Drug
Classes
1-2
3-4
5Switch to
Novel Drug
Classes if
Necessary
Monotherapy
SARS-CoV-2 and COVID-19
Life Cycle of
SARS-CoV-2:
Looking for
Potential
Targets
Eastman et al. 2020, ACS Cent Sci
Source: Gilead Sciences Inc. Warren et al, Nature, 2016
Discovery of Remdesivir (GS-5734)
Gilead library of
nucleosides and
nucleotides
Screening
(CDC)
Prodrug design
(Gilead)
Profiling
(USAMRIID,
CDC)GS-441524 GS-5734
(Remdesivir)
Intracellular Metabolic Pathway
GS-441524GS-5734
NucleotidaseSlow First
Phosphorylation
Hydrolase
Phosphoramidase Nucleotide
Kinases
Alanine-MetaboliteNucleotide
Monophosphate
Active Nucleotide
Triphosphate
Protide by-passes
rate limiting first
phosphorylation
Resistance to Remdesivir ?In Vitro Selection in the Mouse Hepatitis Virus
Agostini et al. 2018, mBio
Remdesivir is a “Delayed Cain-Terminator”
Steric Clash with S861 and Remdesivir
Antibiotics
Alexander Fleming discovered Penicillin in
1928 (Nobel Prize in 1945)
He noticed that bacteria do not
grow near fungus. Though this
experiment was not planned,
he discovered that the fungus
produces a “mold juice” later
referred to as penicillin…
Lactams Inhibit Cell Wall Synthesis
https://basicmedicalkey.com/chemotherapy-of-tuberculosis-mycobacterium-avium-complex-disease-and-leprosy/
Fleming and Antibiotic Resistance
Fleming discovered that bacteria
developed antibiotic resistance whenever too
little penicillin was used or when it was used for too
short a period.
He warned in 1945:
“The time may come when penicillin can be bought
by anyone in the shops. Then there is the danger
that the ignorant man may easily underdose himself
and by exposing his microbes to non-lethal quantities
of the drug make them resistant.”
https://www.gov.uk/.../health-matters-antimicrobial-resistance
UK Economist Jim O’Neill et al. 2014
https://www.gov.uk/.../health-matters-antimicrobial-resistance
https://www.canada.ca…preserving-antibiotics/about-antibiotic-
resistance.html
From AMR Spread between Bacteria…
Barton et al. 2007. Evolution.
https://www.reactgroup.org
Mechanisms of Antibiotic Resistance
Focus on Inactivating Enzymes
Beta-Lactamase
Enzymes
Alternative Treatments: Phage Therapy
Phages Are Viruses that Infect Bacteria
Salmond, G. P. & Fineran, P. C.
Nat. Rev. Microbiol. 13,777–786
(2015).
1Department of Biological Sciences, University of Pittsburgh,
Pittsburgh, PA, USA. 2Great Ormond Street Hospital, London, UK.
3Department of Medicine,
University of California, San Diego, La Jolla, CA, USA. 4These authors
contributed equally: Rebekah M. Dedrick and Carlos A. Guerrero-
Bustamante.
*e-mail: [email protected]; [email protected]
Nature Medicine | 730 VOL 25 | MAY 2019 | 730–733 |
www.nature.com/naturemedicine
A 15-year-old patient with cystic fibrosis and a life-threatening bacterial
infection was treated with a three-phage cocktail following lung
transplantation. Lytic phage derivatives efficiently killed the infectious.
Phage treatment was associated with clinical improvement, although the
athors cannot exclude the possibility that patient gains would have occurred
without phage treatment.
Triple Therapy Killed Antibiotic Resistant Bacteria
Summary
Nucleoside analogues are frequently used antivirals
These compounds target the viral polymerase and
interfere with genome replication
Resistance is selected from a pool of diverse viruses
Lactams are frequently used antibiotics
These compounds interfere with cell wall synthesis
Selection of resistance in bacteria is often based on similar
principles as reported for viruses
Lecture Title: Date:
Discussion Questions
Describe important principles underlying the selection of resistance
in viruses and bacteria, respectively.
What is a fundamentally different mechanism that is used by
Bacteria?
Non-adherence to antimicrobial drug regimens can lead to the
development of resistance. Why?
A combination of antivirals or antibiotics can prevent the
emergence of resistance. Why?
Lecture Title: Date:
Thank You!
Dr. Matthias Götte
Department of Medical Microbiology &
Immunology
Faculty of Medicine & Dentistry
University of Alberta
Email: [email protected]
Lecture Title: Date: